Every year in the United States, >1.25 million people suffer from burns, 6.5 million have chronic skin ulcers caused by pressure, venous stasis or diabetes mellitus and 0.25 million have keloids sufficiently severe to require surgery. Burn treatment costs $1.8 billion per year in the US. The treatment of persons with chronic skin ulcers costs $13 billion per year in the US. The annual cost of diabetic peripheral neuropathy and/or neuropathic foot ulcers in the U.S. is $ 0.8 billion for type I diabetics and $10.1 billion for type II diabetics. Limb-sparing surgical procedures are also widely used. In spite of these large costs for the care and the treatment of diabetic foot ulcers, each year 82,000 limb amputations are still performed on US patients with diabetic ulcers because current therapy is not very effective. These surgical treatments cost about $ 0.3 billion per year in the US. Currently, there is no agent which has been shown to be effective for treating cutaneous wounds. As these costs suggest, there is an urgent need for developing effective agents to accelerate wound healing and reduce scarring or tissue fibrosis in patients with burn injuries, blast injuries, chronic skin ulcers, keloids and other similar disorders. New products to treat these patients will drive the market. Accumulating evidence indicates that TGF-2, a cytokine, provides an ideal target for developing novel therapeutic agents for many types of wounds including chronic wounds. TGF-2 is produced at the wound site and is responsible for recruiting inflammatory cells and fibroblasts to the wound site, inhibiting epithelial cell growth (wound re-epithelialization) and stimulating extracellular matrix synthesis by fibroblasts (fibrosis) at the wound site. In prior studies, we developed a synthetic TGF-2 peptide antagonist (termed TGF-2 peptantagonist) which is the only known synthetic TGF-2 receptor antagonist. TGF-2 peptantagonist can enhance wound healing and reduce scarring in pig skin burn/excision and rabbit skin excision wound models. However, the efficacy of the synthetic TGF-2 peptantagonist is limited by its poor solubility in aqueous solution. This project aims at developing new chemical forms of our TGF-2 peptantagonist with excellent solubility, high tissue penetration ability and potent TGF-2 antagonist activity as drug candidates for treating wounds in humans. In Phase I studies, we have developed two new TGF-2 peptantagonists with rationally engineered properties exhibit high solubility in aqueous solution and are 10-times more potent than the prototype (unmodified) TGF-2 peptantagonist in inhibiting TGF-2 activity in vitro. One of these two new TGF-2 peptantagonists has been shown to potently prevent tissue injury, accelerate wound healing and reduce scarring in several animal injury models. These promising results have provided rationales for the proposed studies in the Phase II project. We hope the clinical availability of these two novel TGF-2 peptantagonists will be commercialized by large pharmaceutical companies, eventually directly benefiting individuals with various types of wounds including normal, impaired and chronic wounds. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop synthetic TGF-2 antagonists into wound healing agents for accelerating wound healing and reducing scarring. The clinical availability of these agents would benefit millions of patients who suffer from various types of wounds including normal, impaired and chronic wounds.